Biomedical subjects

Peng Xiao

Publications and source records attributed to Peng Xiao.

At least 19 recordsLinked to original sources

PubMed2006

The chemokine (C-C-motif) receptor 3 (CCR3) gene is linked and associated with age at menarche in Caucasian females.

Chemokine (C-C-motif) receptor 3 (CCR3), playing an important role in endometrium related metabolic pathways, may influence the onset of menarche. To test linkage and/or association between CCR3 polymorphisms with the variation of age at menarche (AAM) in Caucasian females, we recruited a sample of 1,048 females from 354 Caucasian nuclear families and genotyped 16 SNPs spanning the entire CCR3 gene. Linkage disequilibrium and haplotype blocks were inferred by Haploview. Both single-SNP markers and haplotypes were tested for linkage and/or association with AAM using QTDT (quantitative transmission disequilibrium test). We also tested associations between CCR3 polymorphisms and AAM in a selected random sample of daughters using ANOVA (analysis of variance). We identified two haplotype blocks. Only block two showed significant results. After correction for multiple testing, significant total associations of SNP7, SNP9 with AAM were detected (P = 0.009 and 0.006, respectively). We also detected significant within-family association of SNP9 (P = 0.01). SNP14 was linked to AAM (P = 0.02) at the nominal level. In addition, there was evidence of significant total association and nominal significant linkage (P = 0.008 and 0.03, respectively) with AAM for the haplotype AGA reconstructed by SNP7, SNP9 and SNP13. ANOVA confirmed the results by QTDT. For the first time we reported that CCR3 is linked and associated with AAM variation in Caucasian women. However, further studies are necessary to substantiate our conclusions.

Aging↗

PubMed2006

A genome-wide linkage scan for quantitative trait loci underlying obesity related phenotypes in 434 Caucasian families.

To identify quantitative trait loci (QTLs) that contribute to obesity, we performed a large-scale whole genome linkage scan (WGS) involving 4,102 individuals from 434 Caucasian families. The most pronounced linkage evidence was found at the genomic region 20p11-12 for fat mass (LOD = 3.31) and percentage fat mass (PFM) (LOD = 2.92). We also identified several regions showing suggestive linkage signals (threshold LOD = 1.9) for obesity phenotypes, including 5q35, 8q13, 10p12, and 17q11.

Family↗

PubMed2006

Is a gene important for bone resorption a candidate for obesity? An association and linkage study on the RANK (receptor activator of nuclear factor-kappaB) gene in a large Caucasian sample.

In light of findings that osteoporosis and obesity may share some common genetic determination and previous reports that RANK (receptor activator of nuclear factor-kappaB) is expressed in skeletal muscles which are important for energy metabolism, we hypothesize that RANK, a gene essential for osteoclastogenesis, is also important for obesity. In order to test the hypothesis with solid data we first performed a linkage analysis around the RANK gene in 4,102 Caucasian subjects from 434 pedigrees, then we genotyped 19 SNPs in or around the RANK gene. A family-based association test (FBAT) was performed with both a quantitative measure of obesity [fat mass, lean mass, body mass index (BMI), and percentage fat mass (PFM)] and a dichotomously defined obesity phenotype-OB (OB if BMI > or = 30 kg/m(2)). In the linkage analysis, an empirical P = 0.004 was achieved at the location of the RANK gene for BMI. Family-based association analysis revealed significant associations of eight SNPs with at least one obesity-related phenotype (P < 0.05). Evidence of association was obtained at SNP10 (P = 0.002) and SNP16 (P = 0.001) with OB; SNP1 with fat mass (P = 0.003); SNP1 (P = 0.003) and SNP7 (P = 0.003) with lean mass; SNP1 (P = 0.002) and SNP7 (P = 0.002) with BMI; SNP1 (P = 0.003), SNP4 (P = 0.007), and SNP7 (P = 0.002) with PFM. In order to deal with the complex multiple testing issues, we performed FBAT multi-marker test (FBAT-MM) to evaluate the association between all the 18 SNPs and each obesity phenotype. The P value is 0.126 for OB, 0.033 for fat mass, 0.021 for lean mass, 0.016 for BMI, and 0.006 for PFM. The haplotype data analyses provide further association evidence. In conclusion, for the first time, our results suggest that RANK is a novel candidate for determination of obesity.

Adult↗

PubMed2006

HDC gene polymorphisms are associated with age at natural menopause in Caucasian women.

Histidine decarboxylase gene (HDC) encodes histidine decarboxylase which is the crucial enzyme for the biosynthesis of histidine. Studies have shown that histamine is likely to be involved in the regulation of reproduction system. To find the possible correlation between HDC gene and AANM (age at natural menopause), we selected 265 postmenopausal women from 131 nuclear families and performed a transmission disequilibrium test. Significant within-family associations with AANM for SNP rs854163 and SNP rs854158 of HDC gene were observed (P values=0.0018 and 0.0197, respectively). After 1000 permutations, SNP rs854163 still remained significant within-family association with AANM. Consistently, we also detected a significant within-family association between haplotype block 2 (defined by SNP rs854163 and rs860526) and AANM in the haplotype analyses (P value=0.0397). Our results suggest that the HDC gene polymorphisms are significantly associated with AANM in Caucasian women.

Age Factors↗

PubMed2006

Epistasis between loci on chromosomes 2 and 6 influences human height.

CONTEXT: Human height is a typical and important complex trait, which is determined by both actions and interactions of multiple genes. Although an increasing number of genes or genomic regions have been discovered for their independent effects on height variation, no study has been performed to identify genes or loci that interact to control the trait. OBJECTIVE: This study aimed to search for potential genomic regions that harbor interactive genes underlying human height. METHODS: Here with a sample containing 3726 Caucasians, the largest one ever obtained from a single population of the same ethnicity among genetic linkage studies of human complex traits, we performed variance component linkage analyses of height based on a two-locus epistatic model. We examined pairwise genetic interaction among three regions, 9q22, 6p21, and 2q21, which achieved significant or suggestive linkage signals for height in our recent whole genome scan. RESULTS: Significant genetic interaction between 6p21 and 2q21 was detected, with 2q21 achieving a maximum LOD score of 3.21 (P = 0.0035) under the epistatic model, compared with a maximum LOD score of 1.63 under a two-locus additive model. Interestingly, 6p21 contains a cluster of candidate genes for skeletal growth, suggesting a mechanism whereby 2q21 regulates height through 6p21. CONCLUSION: By providing the first evidence for genetic interaction underlying human height variation, this study further delineated the genetic architecture of human height and contributed to the genetic dissection of human complex traits in general.

Adult↗

PubMed2006

Assessment of genetic linkage and parent-of-origin effects on obesity.

CONTEXT: Obesity is a growing health care problem worldwide and is a major underlying risk factor for common diseases such as diabetes. Parent-of-origin effect has been reported to be involved in the development of obesity. But the genes with imprinting effects related to obesity are largely unknown. OBJECTIVE: The objective of the study was to identify obesity-related genetic loci, both with and without imprinting effects. DESIGN AND SUBJECTS: We conducted genome-wide linkage analyses for obesity with and without consideration of imprinting effects in a large sample including more than 4000 individuals. In addition to body mass index (BMI), we also used a more stringent and accurate obesity definition, which simultaneously considers BMI and percentage of fat mass (PFM) in a gender-specific manner. Simulations were performed to identify the genome-wide significant and suggestive significant thresholds. RESULTS: In nonimprinted linkage analyses, we detected suggestive linkage at 2q31 (LOD = 2.23) and 16q22 (LOD = 1.87) for BMI and 2q37 (LOD = 2.23) for BMI and PFM. Interestingly, 2q37 also achieved a significant maternal linkage with BMI and PFM (LOD=3.34) in imprinted linkage analyses. Imprinted linkage analyses revealed suggestive linkage evidence for BMI at three additional genomic regions, including 3p14 (LOD = 2.20, paternal), 3q24 (LOD = 1.97, maternal), and 19q13 (LOD = 1.81, maternal). CONCLUSION: We reported linkage and imprinting effects for obesity on several chromosome regions and suggested the potential importance of parent-of-origin effects and phenotype definition of obesity in delineating the genetic basis of obesity.

Adipose Tissue↗

PubMed2006

The electrophysiological properties of HVC-RA synaptic transmission in the adult zebra finch in vivo.

The synaptic connection from high vocal center (HVC) to robust nucleus of the arcopallium (RA) is a pivotal part of vocal motor pathway in songbirds. Electrophysiological properties of HVC-RA synaptic transmission in adult male zebra finch (Taeniopygia guttata) in vivo was investigated by using field potential recording method. Following electrical stimulation of HVC, the evoked field potentials recorded in RA were feeble. The results showed that the remarkable paired-pulse facilitation was induced by paired-pulse stimulation at HVC-RA synapses. The results also showed that the evoked field potentials were significantly decreased after a conditioning tetanic stimulation and finally recovered gradually within 15 min, which indicates tetanic stimulation-induced transient depression is present at HVC-RA synaptic transmission. These results suggest that properties of synaptic transmission in this pathway might play a role in controlling song production.

Animals↗

PubMed2006

Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study.

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene, essential for glucose and cholesterol metabolism, may have a role in the aetiology of obesity, an important risk factor for diabetes. PARTICIPANTS AND METHODS: To investigate the association between LRP5 polymorphisms and obesity, 27 single-nucleotide polymorphisms (SNPs), spacing about 5 kb apart on average and covering the full transcript length of the LRP5 gene, were genotyped in 1873 Caucasian people from 405 nuclear families. Obesity (defined as body mass index (BMI) >30 kg/m(2)) and three obesity-related phenotypes (BMI, fat mass and percentage of fat mass (PFM)) were investigated. RESULTS: Single markers (12 tagging SNPs and 4 untaggable SNPs) and haplotypes (5 blocks) were tested for associations, using family-based designs. SNP4 (rs4988300) and SNP6 (rs634008) located in block 2 (intron 1) showed significant associations with obesity and BMI after Bonferroni correction (SNP4: p<0.001 and p = 0.001, respectively; SNP6: p = 0.002 and 0.003, respectively). The common allele A for SNP4 and minor allele G for SNP6 were associated with an increased risk of obesity. Significant associations were also observed between common haplotype A-G-G-G of block 2 with obesity, BMI, fat mass and PFM with global empirical values p<0.001, p<0.001, p = 0.003 and p = 0.074, respectively. Subsequent sex-stratified analyses showed that the association in the total sample between block 2 and obesity may be mainly driven by female subjects. CONCLUSION: Intronic variants of the LRP5 gene are markedly associated with obesity. We hypothesise that such an association may be due to the role of LRP5 in the WNT signalling pathway or lipid metabolism. Further functional studies are needed to elucidate the exact molecular mechanism underlying our finding.

Adult↗

PubMed2006

Genetic linkage of human height is confirmed to 9q22 and Xq24.

Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

Adult↗

PubMed2006

Genomewide linkage scan for quantitative trait loci underlying variation in age at menarche.

CONTEXT: Age at menarche (AAM) is an important anthropological variable that has major implications for a woman's health later in life. Genetic influence has been shown to contribute greatly to AAM, but the specific genetic determinants are largely unknown. OBJECTIVE: The objective of this study was to identify the quantitative trait loci (QTL) underlying the variations in AAM. METHODS: We performed a large-scale, genomewide, linkage scan in 2461 Caucasian women from 402 pedigrees. All subjects were genotyped with 410 microsatellite markers spaced approximately 8.9 cM apart across the human genome. Using the variance component method, we conducted multipoint linkage analyses and two-locus tests for epistatic interaction. RESULTS: The strongest linkage signal was obtained at the genomic region of 22q13 (LOD, 3.70); the other two suggestive linkages were on 22q11 (LOD, 2.68) and 11q23 (LOD, 1.98), respectively. We also detected significant epistatic interaction between genomic regions 22q13 and 3q13. CONCLUSIONS: The identification of QTL and epistatic interaction in a large female sample laid a foundation for independent replication and fine-mapping studies as well as positional and functional candidate gene studies aimed at finding the causal genetic variants and hidden mechanisms concerning the variations in AAM.

Age Factors↗

PubMed2006

Paternal uniparental isodisomy of the entire chromosome 3 revealed in a person with no apparent phenotypic disorders.

Uniparental disomy (UPD) is a rare genetic abnormality. During a whole genome linkage study we identified a case of paternal uniparental isodisomy 3 serendipitously. This is the first ascertained human paternal UPD for chromosome 3 (UPD3pat). The finding of this paternal UPD case of the entire chromosome 3 with no apparent phenotypic disorders suggests that there are no paternal imprinted genes causing rare genetic disorders on chromosome 3.

Alleles↗

PubMed2006

Tests of linkage and association of PTH/PTHrP receptor type 1 gene with bone mineral density and height in Caucasians.

Parathyroid hormone/parathyroid hormone-related peptide receptor type 1 (PTHR1) plays an important role in calcium metabolism. It was previously shown to influence variation in bone mineral density (BMD). To investigate its importance in a typical U.S. Caucasian population, we tested linkage or association of the PTHR1 gene with BMD and height. Altogether, 1873 subjects from 405 Caucasian nuclear families were studied. BMD was measured at the lumbar spine (L1-L4) and total hip (femoral neck, trochanter, and intertrochanter regions). Four single nucleotide polymorphisms (SNPs) in the PTHR1 gene were genotyped. Sixteen haplotypes were reconstructed. Only two major haplotypes had frequencies >3% and were thus used for the analysis. Analyses were performed for BMD and height in the total sample and for peak BMD (PBMD) achieved in offspring subjects aged 20-50 in a subsample of 387 nuclear families. We found suggestive evidence for total association between haplotype 13 (AATG) and hip PBMD (P = 0.031). For height, evidence of within-family association was suggested for SNP1, SNP2, and haplotype 4 (GGCA) (P < or = 0.05). Our findings suggest that the PTHR1 gene may be important for PBMD, height variation, or both, although the significance is dampened by correction for multiple testing.

Absorptiometry, Photon↗

PubMed2006

Competitive study of monoclonal antibodies against the HIV-1 Gp41 core structure.

Monoclonal antibodies (MAbs) 50.69, 98.6, and T26 bind specifically to the core structure of the human immunodeficiency virus type 1 (HIV-1) envelope transmembrane glycoprotein (gp41). To clarify the specificity of the anti-core structure MAbs, we performed competitive assays using the MAbs to the H9 human T cell line infected with the IIIB strain of HIV-1 (H9/IIIB). Bound MAb 50.69 inhibited MAb 98.6 binding unidirectionally. The reason for the unidirectional cross competition between MAbs 50.69 and 98.6 is not clear, but these results help to define the antigenic structure of gp41 on the surface of infected cells.

Antibodies, Monoclonal↗

PubMed2006

Molecular genetic studies of gene identification for osteoporosis: a 2004 update.

This review summarizes comprehensively the most important and representative molecular genetics studies of gene identification for osteoporosis published up to the end of December 2004. It is intended to constitute a sequential update of our previously published review covering the available data up to the end of 2002. Evidence from candidate gene association studies and genome-wide linkage studies in humans, as well as quantitative trait locus mapping animal models are reviewed separately. Studies of transgenic and knockout mice models relevant to osteoporosis are summarized. An important extension of this update is incorporation of functional genomic studies (including DNA microarrays and proteomics) on osteogenesis and osteoporosis, in light of the rapid advances and the promising prospects of the field. Comments are made on the most notable findings and representative studies for their potential influence and implications on our present understanding of genetics of osteoporosis. The format adopted by this review should be ideal for accommodating future new advances and studies.

Animals↗

PubMed2006

Genomic regions identified for BMD in a large sample including epistatic interactions and gender-specific effects.

UNLABELLED: A genome-wide linkage scan was conducted using a large white sample to identify QTLs for BMD. We found QTLs in the total sample and the gender-specific subgroups, as well as significant epistatic interactions underlying BMD variations. INTRODUCTION: Low BMD is an important risk factor for osteoporosis and under strong genetic control. MATERIALS AND METHODS: To identify quantitative trait loci (QTLs) for regulation of BMD, we performed a large-scale whole genome linkage scan (WGS) involving 4126 individuals from 451 families. In addition to the conventional linkage analyses in the total combined sample of males and females, we conducted epistatic interaction analyses and gender-specific linkage analyses. RESULTS: Significant linkage was detected on 5q23 for wrist BMD (LOD = 3.39) and 15q13 for female spine BMD (LOD = 4.49). For spine BMD, we revealed significant epistatic interactions between 3p25 and 2q32 (p = 0.0022) and between 3p25 and 11q23 (p = 0.0007). We replicated several genomic regions that showed linkage with BMD in previous studies by others and ours, such as 3p21, 1p36, and Xq27. CONCLUSIONS: This study highlights the importance of large sample size, incorporation of epistatic interaction, and consideration of gender-specific effects in identifying QTLs for BMD variation. The results of this study provide a foundation for the future fine mapping and gene identification in our population.

Bone Density↗

PubMed2006

Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction.

UNLABELLED: Many "novel" osteoporosis candidate genes have been proposed in recent years. To advance our knowledge of their roles in osteoporosis, we screened 20 such genes using a set of high-density SNPs in a large family-based study. Our efforts led to the prioritization of those osteoporosis genes and the detection of gene-gene interactions. INTRODUCTION: We performed large-scale family-based association analyses of 20 novel osteoporosis candidate genes using 277 single nucleotide polymorphisms (SNPs) for the quantitative trait BMD variation and the qualitative trait osteoporosis (OP) at three clinically important skeletal sites: spine, hip, and ultradistal radius (UD). MATERIALS AND METHODS: One thousand eight hundred seventy-three subjects from 405 white nuclear families were genotyped and analyzed with an average density of one SNP per 4 kb across the 20 genes. We conducted association analyses by SNP- and haplotype-based family-based association test (FBAT) and performed gene-gene interaction analyses using multianalytic approaches such as multifactor-dimensionality reduction (MDR) and conditional logistic regression. RESULTS AND CONCLUSIONS: We detected four genes (DBP, LRP5, CYP17, and RANK) that showed highly suggestive associations (10,000-permutation derived empirical global p < or = 0.01) with spine BMD/OP; four genes (CYP19, RANK, RANKL, and CYP17) highly suggestive for hip BMD/OP; and four genes (CYP19, BMP2, RANK, and TNFR2) highly suggestive for UD BMD/OP. The associations between BMP2 with UD BMD and those between RANK with OP at the spine, hip, and UD also met the experiment-wide stringent criterion (empirical global p < or = 0.0007). Sex-stratified analyses further showed that some of the significant associations in the total sample were driven by either male or female subjects. In addition, we identified and validated a two-locus gene-gene interaction model involving GCR and ESR2, for which prior biological evidence exists. Our results suggested the prioritization of osteoporosis candidate genes from among the many proposed in recent years and revealed the significant gene-gene interaction effects influencing osteoporosis risk.

Adult↗

PubMed2005

Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis.

UNLABELLED: A genome-wide screen was conducted using a large white sample to identify QTLs for FNCS geometry. We found significant linkage of FNCS parameters to 20q12 and Xq25, plus significant epistatic interactions and sex-specific QTLs influencing FNCS geometry variation. INTRODUCTION: Bone geometry, a highly heritable trait, is a critical component of bone strength that significantly determines osteoporotic fracture risk. Specifically, femoral neck cross-sectional (FNCS) geometry is significantly associated with hip fracture risk as well as genetic factors. However, genetic research in this respect is still in its infancy. MATERIALS AND METHODS: To identify the underlying genomic regions influencing FNCS variables, we performed a remarkably large-scale whole genome linkage scan involving 3998 individuals from 434 pedigrees for four FNCS geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). The major statistical approach adopted is the variance component method implemented in SOLAR. RESULTS: Significant linkage evidence (threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20q12 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). We also identified eight suggestive linkage signals (threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. The above findings were supported by principal component linkage analysis. Of them, 20q12 was of particular interest because it was linked to multiple FNCS geometry traits and significantly interacted with five other genomic loci to influence CSA variation. The effects of 20q12 on FNCS geometry were present in both male and female subgroups. Subgroup analysis also revealed the presence of sex-specific quantitative trait loci (QTLs) for FNCS traits in the regions such as 2p14, 3q26, 7q21 and 15q21. CONCLUSIONS: Our findings laid a foundation for further replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming at eventually finding the causal genetic variants and hidden mechanisms concerning FNCS geometry variation and the associated hip fractures.

Adult↗

PubMed2005

Mapping quantitative trait loci for cross-sectional geometry at the femoral neck.

UNLABELLED: A genome-wide linkage scan was performed in a sample of 79 multiplex pedigrees to identify genomic regions linked to femoral neck cross-sectional geometry. Potential quantitative trait loci were detected at several genomic regions, such as 10q26, 20p12-q12, and chromosome X. INTRODUCTION: Bone geometry is an important determinant of bone strength and osteoporotic fractures. Previous studies have shown that femoral neck cross-sectional geometric variables are under genetic controls. To identify genetic loci underlying variation in femoral neck cross-sectional geometry, we conducted a whole genome linkage scan for four femoral neck cross-sectional geometric variables in 79 multiplex white pedigrees. MATERIALS AND METHODS: A total of 1816 subjects from 79 pedigrees were genotyped with 451 microsatellite markers across the human genome. We performed linkage analyses on the entire data, as well as on men and women separately. RESULTS: Significant linkage evidence was identified at 10q26 for buckling ratio (LOD = 3.27) and Xp11 (LOD = 3.45) for cortical thickness. Chromosome region 20p12-q12 showed suggestive linkage with cross-sectional area (LOD = 2.33), cortical thickness (LOD = 2.09), and buckling ratio (LOD = 1.94). Sex-specific linkage analyses further supported the importance of 20p12-q12 for cortical thickness (LOD = 2.74 in females and LOD = 1.88 in males) and buckling ratio (LOD = 5.00 in females and LOD = 3.18 in males). CONCLUSIONS: This study is the first genome-wide linkage scan searching for quantitative trait loci underlying femoral neck cross-sectional geometry in humans. The identification of the genes responsible for bone geometric variation will improve our knowledge of bone strength and aid in development of diagnostic approaches and interventions for osteoporotic fractures.

Absorptiometry, Photon↗